Recently, much attention in the patent and technical literature has been directed to delivery of drug or agent through intact skin or organ surfaces by either passive processes, e.g., diffusion, or active processes, e.g., electrotransport. The present invention relates to both such transdermal processes, but will be here described with primary reference to active transdermal processes. The term "electrotransport" as used herein refers generally to the delivery of a beneficial agent (e.g., a drug) through a biological membrane, such as skin, mucous membrane, or nails. The delivery is induced or aided by application of an electrical potential. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of a human body by electrotransport delivery through the skin. A widely used electrotransport process, electromigration (also called iontophoresis), involves the electrically induced transport of charged ions. Another type of electrotransport, electroosmosis, involves the flow of a liquid under the influence of an electric field, the liquid containing the agent to be delivered. Still another type of electrotransport process, electroporation, involves the formation of transiently-existing pores in a biological membrane by the application of an electric field. An agent can be delivered through the pores either passively (i.e., without electrical assistance) or actively (i.e., under the influence of an electric potential). However, in any given electrotransport process, more than one of these processes may be simultaneously occurring.
Accordingly, the term "electrotransport", as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture of charged and uncharged species, regardless of the specific mechanism or mechanisms by which the agent actually is transported.
Electrotransport devices use at least two electrodes that are in electrical contact with some portion of the skin, nails, mucous membrane, organ surfaces, or other surface of the body. One electrode, commonly called the "donor" or "active" electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, i.e., a cation, then the anode is the active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if an agent is negatively charged, i.e., an anion, the cathode is the donor electrode. Additionally, both the anode and cathode may be considered donor electrodes if both anionic and cationic agent ions, or if uncharged dissolved agents, are to be delivered.
Furthermore, electrotransport delivery systems generally require at least one reservoir or source of the agent to be delivered to the body. Examples of such donor reservoirs include a pouch or cavity, a porous sponge or pad, and a hydrophilic polymer or a gel matrix. Such donor reservoirs are electrically connected to, and positioned between, the anode electrode or cathode electrode (depending upon the agent) and the body surface, to provide a fixed or renewable source of one or more agents or drugs. Electrotransport devices also have an electrical power source such as one or more batteries. Typically, one pole of the power source is electrically connected to the donor electrode, while the opposite pole is electrically connected to the counter electrode. In addition, some electrotransport devices have an electrical controller that controls the current applied through the electrodes, thereby regulating the rate of agent delivery. Furthermore, passive flux control membranes, adhesives for maintaining device contact with a body surface, insulating members, and impermeable backing members are some other potential components of an electrotransport device.
All electrotransport agent delivery devices utilize an electrical circuit to connect electrically the power source (e.g., a battery) and the electrodes. In very simple devices, such as those disclosed in Ariura et al. U.S. Pat. No. 4,474,570, the "circuit" is merely an electrically conductive wire used to connect the battery to an electrode. Other devices use a variety of electrical components to control the amplitude, polarity, timing, waveform shape, etc. of the electric current supplied by the power source. See, for example, McNichols et al. U.S. Pat. No. 5,047,007.
To date, commercial transdermal electrotransport drug delivery devices (e.g., the Phoresor, sold by Iomed, Inc. of Salt Lake City, Utah; the Dupel Iontophoresis System sold by Empi, Inc. of St. Paul, Minn.; the Webster Sweat Inducer, model 3600, sold by Wescor, Inc. of Logan, Utah) have generally utilized a desk-top electrical power supply unit and a pair of skin contacting electrodes. The donor electrode reservoir contains a drug solution while the counter electrode reservoir contains a solution of a bio-compatible electrolyte salt. The "satellite" electrodes are connected to the electrical power supply unit by long (e.g., 1-2 meters) electrically conductive wires or cables. Examples of desk-top electrical power supply units which use "satellite" electrode assemblies are disclosed in Jacobsen et al. U.S. Pat. No. 4,141,359 (see FIGS. 3 and 4); LaPrade U.S. Pat. No. 5,006,108 (see FIG. 9); and Maurer et al. U.S. Pat. No. 5,254,081 (see FIGS. 1 and 2).
More recently, small, self-contained electrotransport delivery devices or assemblies, adapted to be worn on the skin for extended periods of time, have been proposed. The electrical components of such miniaturized electrotransport drug delivery devices are also preferably miniaturized, and may be in the form of either integrated circuits (i.e., microchips) or small printed circuits. Electronic components, such as batteries, resistors, pulse generators, capacitors, etc., are electrically connected to form an electronic circuit that controls the amplitude, polarity, timing, waveform shape (and other parameters) of the electric current supplied by the power source. Such small self-contained electrotransport delivery devices are disclosed, for example, in Tapper U.S. Pat. No. 5,224,927; Haak et al. U.S. Pat. No. 5,203,768; Sibalis et al. U.S. Pat. No. 5,224,928; and Haynes et al. U.S. Pat. No. 5,246,418.
In contrast with electrotransport transdermal devices, passive transdermal devices are generally much simpler. For example, Gale et al. U.S. Pat. No. 4,588,580 discloses a transdermal drug delivery device which delivers a therapeutic amount of a drug, e.g., fentanyl, by passive diffusion through intact skin. As is described in the Gale et al. '580 patent, a passive transdermal therapeutic system comprises a pouch formed from a drug/solvent/gel impermeable backing, a drug elution rate-controlling membrane which, with the pouch, forms a drug reservoir. The drug reservoir contains a dissolved or suspended drug therein. The entire assembly is held in place on a patient's skin by a biocompatible adhesive layer located on the skin-contacting side of the device.
One drawback with small (i.e., wearable) unitary electrotransport systems which are manufactured with a predetermined amount of drug in the device, is that once the drug is depleted, the entire device must be discarded. Such integrated devices, of necessity, have components or subassemblies, e.g., batteries, drug reservoirs and electrical subassemblies, all of which are simultaneously discarded into the environment at the time of device disposal. Further, transdermal electrotransport delivery of extremely potent drugs such as narcotic analgesics, which are potentially addictive, can have serious side effects, e.g., respiratory depression. Thus, availability of safe (or even regulated) disposal of drug-containing components or subcomponents of self-contained, wearable, transdermal (especially electrotransport) devices will permit such devices to become more commercially acceptable.